A-Hydroxyketones benzoins

DAVIDSON Oxazole Synthesis Synthesis of Iriaryl oxazoles from a-hydroxyketones (benzoins)... 

This generates a nucleophile which is able to undergo nucleophilic addition to another molecule of benzaldehyde. After proton transfers, this intermediate collapses with loss of cyanide to give a hydroxyketone (benzoin) product. 

In this experiment, benzil is prepared by the oxidation of an a-hydroxyketone, benzoin. This experiment uses the benzoin prepared in Experiment 32A and is the second step in the multistep synthesis. This oxidation can be done easily with mild oxidizing agents such as Fehling s solution (alkaline cupric tartrate complex) or copper sulfate in pyridine. In this experiment, the oxidation is performed with nitric acid. 

The a series uses benzaldehyde as a starting material, which is first converted to the a-hydroxyketone benzoin in Experiment [Ala]. Benzoin is then oxidized to benzfl (Experiment [A2a]). Benzil (along with diphenylacetone) is used in the construction of tetraphenylcyclopentadienone in Experiment [A3a], the third and last of the Sequence Aa intermediates. 

Under Mukaiyama s conditions aromatic a-hydroxyketones (benzoin, 4,4 -dimethylbenzoin and 4,4 -dimethoxybenzoin [anisoin]) are readily oxidized by dioxygen at room temperature in the presence of excess aldehyde or aldoacetal with catalytic amounts of Co(acac)2 or Fe(acac)3 under homogeneous conditions . The stoichiometric equation is shown in Figure 55. 

Both the diketone and the cleavage products were shown to arise from an a-hydroxyketone intermediate (benzoin) 9. 

Nicolaou and coworkers reported efficient enantioselective syntheses of ( )-kinamycin C (3), ( )-kinamycin F (6), and ( )-kinamycin J (10) [39], Nicolaou s retrosyntheses of these targets are shown in Scheme 3.13. The authors envisioned that all three metabolites could be accessed from the common precursor 82. The a-hydroxyketone function of 82 was envisioned to arise from an intramolecular benzoin reaction of the ketoaldehyde 83. This key bond disconnection would serve to forge the cyclopentyl ring of the kinamycin skeleton. The ketoaldehyde 83 was deconstructed by an Ullmann coupling of the aryl bromide 84 and the a-iodoenone 85. The latter were anticipated to arise from the bromojuglone derivative 86 and the enantiomerically enriched enone 87, respectively. 

Trisubstituted imidazoles have been synthesized from 1,2-diketones or a-hydroxyketones with ammonium acetate in very short reaction times with excellent yields in the presence of l,l,3,3-VAr V ,(V -tetramethylguanidinium trifluoroacetate as an ionic liquid <06SC65>. Iodine acted as an efficient catalyst in the synthesis of 1,2,4,5-tetraarylimidazoles 93 using benzoin 91,... 

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

Benzoin condensation. Aromatic aldehydes when treated with an alkali cyanide, usually in aqueous solution, undergo condensation to the a-hydroxyketone or benzoin. The best known example is the conversion of benzaldehyde to benzoin ... 

The Benzoin Condensation is a coupling reaction between two aldehydes that allows the preparation of a-hydroxyketones. The first methods were only suitable for the conversion of aromatic aldehydes. 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

Formamidine reacts with a-hydroxyketones95 and a-haloketones62 to yield oxazoles and imidazoles. Normally the formamidine is liberated from its hydrochloride by the addition of sodium butoxide in n-butanol. It is interesting to note that in the reaction with a-hydroxyketones, the aliphatic acyloins yielded mainly imidazoles (35-68% yield), whereas the benzoins gave mainly oxazoles (67-80%).95 Unlike formamidine, acetamidine and benzamidine react with both aliphatic acyloins and with benzoins to yield imidazoles exclusively.65 Bredereck65 explains the reactions as follows ... 

When amidines or guanidines cyclize in the presence of a-functionalized carbonyl reagents they form imidazoles with a variety of 1-, 2-, 4- and 5-substituents [1, 2]. Formamldine will react with a-hydroxy- [8] or a-halogenoketones [9], to give mixtures of oxazolcs and imidazoles. Usually, the formamidine is liberated from its hydrochloride by treatment with sodium butoxide in butanol. When the two-carbon synthon is an a-hydroxyketone the aliphatic members mainly form imidazoles (35-70%), while benzoins give oxazoles (67-80%) preferentially [8], The competing pathways are shown in Scheme 4.3.1. 

Benzoin Condensation. This involves the reaction of two molecules of aromatic aldehyde having no a-hydrogen with the formation of an a-hydroxyketone. The reaction is catalyzed by cyanide ion. 

Recently, the benzoin condensation of aromatic or heteroaromatic aldehydes (in the absence of VOCs and bases) catalysed by NHCs, obtained by cathodic reduction of RTILs, has been reported. a-Hydroxyketones have been isolated in good to elevated yields, in short reaction time. No a-hydroxyketones have been obtained from linear or short-branched aldehydes instead aldol products and carbene-aldehyde adducts have been isolated in elevated yields (Scheme 16.22) [150,151]. 

When the reaction is carried out in the presence of a trace of a Lewis acid, e.g. FeCl3, the phosphitylation of an a-hydroxyketone, e.g. benzoin, leads not to a phosphite ester, but to a (2-oxoalkyl)phosphonic diester there appears to be, as yet, little information on the scope of this procedure ... 

Symmetrical and unsymmetrical benzoins have been rapidly oxidized to benzils in high yields using solid reagent systems, copper(II) sulfate-alumina [125] or Oxone -wet alumina [125, 126] under the influence of microwaves (Scheme 8.49). Conventionally, the oxidative transformation of a-hydroxyketones to 1,2-diketones is accomplished by reagents such as nitric acid, Fehling s solution, thallium(III) nitrate (TTN), ytterbium(III) nitrate, ammonium chlorochromate-alumina and Clay-fen. In addition to the extended reaction time, most of these processes suffer from drawbacks such as the use of corrosive acids and toxic metals that generate undesirable waste products. 

In the enzymatic aldol reaction, the role of the donor and acceptor is strictly determined by the specificity of the enzyme and only raie coupling product can be obtained. In contrast, the possible product range is more complex in acyloin and benzoin reactions If only a single aldehyde species is used as substrate, only one product can be obtained via homocoupling however, a pair of regioisomeric a-hydroxyketones can be obtained via heterocoupling, when two different aldehydes are used, the ratio of which is determined by the choice of substrates (e.g., benzoyl formate vs. benzaldehyde, pyruvate vs. acetaldehyde), and the specificites of enzymes, respectively (Scheme 2.198). 

Purpose. One of the classic reactions of organic chemistry, the benzoin condensation, is carried out. You will examine the properties of the a-hydroxyketone product of this well-known reaction. The particular a-hydroxyketone generated in this experiment is the compound from which the reaction gains its name, benzoin. 

Indium (III) bromide has been shown to catalyze the azidation of a-hydroxyketones with trimethylsilyl azide. The conversion is best done with strong electron-donating groups at the a-position. For example, benzoin (99) under the reaction conditions gives... 

A -Heterocyclic carbenes represent valuable organocatalysts for the enantioselective cross-benzoin type condensation between aldehydes and ketones, giving a-hydroxyketones derivatives (Scheme 7.24) [40],... 

The benzoin condensation is the coupling of two aldehyde molecules to give an a-hydroxyketone (acyloin) product. In its most classical form, the homocoupling of benzaldehyde gives the parent benzoin (R = R = Ph). Contemporary modifications of the benzoin condensation include the use of acylsilanes as well as imine derivatives in place of one aldehyde partner. ... 

Modified benzoin condensations in which the acyl acceptor is not an aldehyde constitute a variation of the classical cross-benzoin condensation. Aldehydes and ketones can be coupled in an intramolecular annulation reaction to give tertiary a-hydroxyketones. The selective cross-coupling of... 

In the template reactions, acetone can be replaced by the preformed aldol, diacetone alcohol, and also the a, P-unsaturated ketone mesityl oxide.90-93 The use of hydroxyketones can be extended to include benzoins, provided that the l,3-diaminopropanenickel(II) complex is used (equation 13).91... 

The product is a 2-hydroxyketone, and when starting with benzaldehyde is called benzoin, which gives this reaction its name, namely the benzoin condensation. Notice that the cyanide ion is acting as a catalyst in this reaction, and so is not consumed. 

An anion may be formed from a symmetrical acid anhydride by using the carboxylate anion of the corresponding acid as the base. This anion may then be reacted with an aldehyde, such as benzaldehyde, to yield as the initial product a mixed anhydride. Dehydration and hydrolysis often follow to result in an a, P-un saturated acid. This is the Perkin reaction. In the benzoin condensation, benzaldehyde is treated with cyanide ion to form an anion, which then attacks another benzaldehyde molecule to form, after the elimination of the original cyanide ion, a 2-hydroxyketone. 

Benzoin condensation The reaction between two aromatic aldehydes with no a-hydrogens in the presence of NaCN, to give the 2-hydroxyketone adduct. 

Dioh. Acyclic 2-hydroxyketones and a-diketones undergo ultrasound-assisted reduction with LilnH (prepared from InBrj and LiH) in a highly diastereoselective manner. For example, benzoin is converted to the meso-diol exclusively. 

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